Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2 has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
Recently, there has been significant research into some of the roles of cyclooxygenase-2. It has been found that COX-2 is upregulated in benign and malignant tumors (K. Subbaramaiah et al., Proc. Soc. Exp. Biol. Med., 216, 201 (1997)) including lung cancer (T. Hida et al., Anticancer Res., 18, 775-82 (1998)), Barrett's esophagus (K. Wilson, Cancer Res., 58, 2929-34 (1998)) and skin cancer (S. Buckman et al., Carcinogenesis, 19, 723-29 (1998)). It is expressed in airway cells with implication in asthma (P. Barnes et al., Lung Biol. Health Dis., 114, 111-27 (1998)). Cox-2 also has a role in pre-term labor, angiogenesis (M. Tsujii et al. Cell, 93, 705-16 (1998)), vascular rejection (M. Bustos, J. Clin. Invest., 100, 1150-58 (1997)), HIV induced apoptosis (G. Bagetta et al., Biochem. Biophys. Res. Commun., 244, 819-24 (1998)), neurodegeneration (T. Sandhya et al., Brain Res., 788, 223-31 (1998)), inflammatory bowel disease, colitis, (I. Singer et al., Gastroenterology, 115, 297-306 (1998)), cerebral ischemia (S. Nogawa et al., Proc. Natl. Acad. Sci., 95, 10966-71 (1998)), hypertension (A. Nasjletti, Hypertension, 31, 194-200 (1997)), among others.
Drugs that inhibit cyclooxygenase affect colon cancer (T. Kawamori et al., Cancer Res., 58, 409-12 (1998)), allergic neuritis (K. Miyamoto et al., Neuro Report, 9, 2331-4 (1998)), dementia, burn infections (M. Shoup, J. Trauma: Inj., Infec., Crit care, 45, 215-21 (1998)), cytomegalovirus infectivity (E. Speir et al., Circ. Res., 83, 210-16 (1998)), lumbago (H. Bosch, Curr. Med. Res. Opin., 14, 29-38 (1997)), among others.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel benzopyran, dihydroquinoline, benzothiopyran and dihydronapthalene derivatives disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The substituted benzopyran, dihydroquinoline, benzothiopyran and dihydronapthalene derivatives disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
U.S. Pat. No. 5,618,843, to Fisher et al., generically describes acid substituted bicyclic moieties as IIb/IIIA antagonists. WO 94/13659, published Jun. 23, 1994, describes fused benzo compounds for the treatment of CNS disorders. Manrao et al. (J. Indian. Counc. Chem., 12, 38-41 (1996)) describes carboxy coumarinimide derivatives and their antifungal activity. U.S. Pat. No. 5,348,976, to Shibata et al., describes amide substituted benzopyrans as antifungals.
WO96/40110, published Dec. 19, 1996, describes benzopyran derivatives as tyrosine kinase modulators. Loiodice et al. (Tetrahedron, 6, 1001-11 (1995)) describe the preparation of 6-chloro-2,3-dihydro-4H-1-benzopyran carboxylic acids.
Clemence et al. (J. Med. Chem., 31, 1453-62, (1988)) describe 4-hydroxy-3-quinolinecarbooxylic acids as starting material in the preparation of antiinflammatories. Lazer, et al. (J. Med. Chem., 40, 980-89 (1997)) describe benzothiopyran carboxylates as starting material in the preparation of antiinflammatories.
U.S. Pat. No. 5,281,720, to Young et al., describes naphthoic acids as lipoxygenase inhibitors. U.S. Pat. No. 5,348,976, to Shibata et al., describes amide substituted benzopyrans as antifungals. U.S. Pat. No. 5,004,744, to Weissmiller et al., describes 2H-benzopyran-3-carboxylic acid as an intermediate for pesticides. U.S. Pat. No. 4,814,346, to Albert et al., describes 3-phenylbenzopyrans as 5-lipoxygenase inhibitors. U.S. Pat. No. 4,761,425, to Girard and Rokach, describes 4-oxo-benzopyrans as leukotriene antagonists. U.S. Pat. No. 4,609,744, to Young et al., describes 4-oxo-benzopyran-carboxylic acids as leukotriene antagonists. U.S. Pat. No. 5,082,849, to Huang et al., describes 4-oxo-benzopyrans as leukotriene antagonists. WO95/07274, published Mar. 16, 1996, describes 2H-benzopyran-3-carboxylic acid as intermediates. WO88/04654, published Jun. 30, 1988, describes 2H-benzopyran-3-carboxylic acid as intermediates. EP412,939, published Feb. 13, 1991, describes substituted chromenes as 5-lipoxygenase inhibitors. JP2-22272 describes benzopyran-3-carboxylic acids. JP59-29681 describes 8-methoxy-benzopyran-3-carboxylic acid as an intermediate. Bunting et al (Can. J. Chem., 62, 1301-07 (1984)) describes the synthesis of 2-hydroxy-1,2-dihydro quinolines. Ukhin et al (Izv. Akad. Nauk. Ser. Khim., 5, 1222-28 (1996)) describe the synthesis of [2-morpholino-6-nitrobenzopyran]-3-carboxylate. Gupta et al. (Indian J. Chem., 21B, 344-347 (1982)) describe chromene-3-carboxylic acid as an intermediate in the preparation of centrally acting muscle relaxants. Rene and Royer (Eur. J. Med. Chem. -Chim. Ther., 10, 72-78 (1975)) describe the preparation of chromene-3-carboxylic acid. U.S. Pat. No. 4,665,202, to Rimbault et al., describes 2-phenyl substituted flavenes and thioflavenes as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,250,547, to Lochead et al., describes benzopyran derivatives as 5-lipoxygenase inhibitors. Satoh et al. [J. Med. Chem., 36, 3580-94 (1993)] describe substituted chromenes as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,155,130, to Stanton et al. describes substituted chromenes as 5-lipoxygenase inhibitors, and specifically 6-benzyloxy-2H-benzopyran-3-carboxylic acid as an intermediate.
However, compounds of the current invention have not been described as antiinflammatory cyclooxygenase inhibitors.